Project Summary The hippocampus is a brain structure critical for learning, memory, and emotional regulation, whose function is disrupted in neurological and psychiatric disorders including Alzheimer disease (AD) and posttraumatic stress disorder (PTSD). To function properly, the hippocampus requires neurogenesis, the continual division of new neurons and the integration of these neurons into the existing circuitry. The survival and differentiation of these new neurons is highly dependent on experience. Exposure to enriched environments (EEs), consisting of large arenas with objects to explore and opportunities for learning and exercise, leads to increased hippocampal neurogenesis, and concomitant decreases in anxiety- and depression-like behaviors and improved performance on memory tests. However, disentangling the effects of exercise versus enrichment on hippocampal neurogenesis has proven challenging. In the modern age of technology, it is natural to wonder how computer-based virtual reality (VR) may influence the structure and function of the hippocampus, and in particular, how it may be used to improve memory and emotional control in healthy and pathological states. VR training has demonstrated clinical benefit in slowing age-related cognitive decline and in the diagnosis and treatment AD and PTSD. Yet, little remains known about how immersive VR experiences influence the physiology and network activity of the hippocampus. We developed a novel, programmable, and interactive VR system for experimental mice that allows us to investigate the effects of VR exposure on the brain and behavior. Using this system, I found in my preliminary study that mice exposed to an enriched virtual environment (EVE) exhibited increased hippocampal activation and neurogenesis, as compared to mice exposed to an impoverished virtual environment (IVE). One advantage of my system is the capability to build complex virtual worlds in which mice can explore in a tightly exercise- controlled fashion. In this proposal, I seek to determine 1) whether virtual spatial navigation requires hippocampal neurogenesis; 2) whether the complexity of, and exploration time within a VR environment impact hippocampal neurogenesis, memory function and anxiety-like behavior; and 3) how activity of mature dentate granule cells of the hippocampal circuit modulates neurogenesis in an EVE context. Understanding how experience shapes the neural pathways underlying learning and memory is crucial to the eventual development of non-pharmacological interventions for diseases that affect the hippocampus, and normal age-related cognitive decline. Results from this study will provide insight into the future development of computer programs and web-based applications that can prevent and treat age-related cognitive decline, and hold promise for the treatment of a variety of neuropsychiatric disorders.